RESUMEN
Brain iron overload and decreased integrity of the dopaminergic system have been independently reported as brain substrates of cognitive decline in aging. Dopamine (DA), and iron are co-localized in high concentrations in the striatum and prefrontal cortex (PFC), but follow opposing age-related trajectories across the lifespan. DA contributes to cellular iron homeostasis and the activation of D1-like DA receptors (D1DR) alleviates oxidative stress-induced inflammatory responses, suggesting a mutual interaction between these two fundamental components. Still, a direct in-vivo study testing the iron-D1DR relationship and their interactions on brain function and cognition across the lifespan is rare. Using PET and MRI data from the DyNAMiC study (n=180, age=20-79, %50 female), we showed that elevated iron content was related to lower D1DRs in DLPFC, but not in striatum, suggesting that dopamine-rich regions are less susceptible to elevated iron. Critically, older individuals with elevated iron and lower D1DR exhibited less frontoparietal activations during the most demanding task, which in turn was related to poorer working-memory performance. Together, our findings suggest that the combination of elevated iron load and reduced D1DR contribute to disturbed PFC-related circuits in older age, and thus may be targeted as two modifiable factors for future intervention.
Asunto(s)
Dopamina , Memoria a Corto Plazo , Femenino , Adulto , Humanos , Adulto Joven , Persona de Mediana Edad , Anciano , Dopamina/fisiología , Memoria a Corto Plazo/fisiología , Longevidad , Hierro , Receptores de Dopamina D1/metabolismo , Corteza Prefrontal/fisiología , Trastornos de la MemoriaRESUMEN
Concomitant exploration of structural, functional, and neurochemical brain mechanisms underlying age-related cognitive decline is crucial in promoting healthy aging. Here, we present the DopamiNe, Age, connectoMe, and Cognition (DyNAMiC) project, a multimodal, prospective 5-year longitudinal study spanning the adult human lifespan. DyNAMiC examines age-related changes in the brain's structural and functional connectome in relation to changes in dopamine D1 receptor availability (D1DR), and their associations to cognitive decline. Critically, due to the complete lack of longitudinal D1DR data, the true trajectory of one of the most age-sensitive dopamine systems remains unknown. The first DyNAMiC wave included 180 healthy participants (20-80 years). Brain imaging included magnetic resonance imaging assessing brain structure (white matter, gray matter, iron), perfusion, and function (during rest and task), and positron emission tomography (PET) with the [11 C]SCH23390 radioligand. A subsample (n = 20, >65 years) was additionally scanned with [11 C]raclopride PET measuring D2DR. Age-related variation was evident for multiple modalities, such as D1DR; D2DR, and performance across the domains of episodic memory, working memory, and perceptual speed. Initial analyses demonstrated an inverted u-shaped association between D1DR and resting-state functional connectivity across cortical network nodes, such that regions with intermediate D1DR levels showed the highest levels of nodal strength. Evident within each age group, this is the first observation of such an association across the adult lifespan, suggesting that emergent functional architecture depends on underlying D1DR systems. Taken together, DyNAMiC is the largest D1DR study worldwide, and will enable a comprehensive examination of brain mechanisms underlying age-related cognitive decline.
Asunto(s)
Envejecimiento Cognitivo , Conectoma , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Cognición/fisiología , Dopamina , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Estudios ProspectivosRESUMEN
Intracellular iron is essential for many neurobiological mechanisms. However, at high concentrations, iron may induce oxidative stress and inflammation. Brain iron overload has been shown in various neurodegenerative disorders and in normal aging. Elevated brain iron in old age may trigger brain dysfunction and concomitant cognitive decline. However, the exact mechanism underlying the deleterious impact of iron on brain function in aging is unknown. Here, we investigated the role of iron on brain function across the adult lifespan from 187 healthy participants (20-79 years old, 99 women) who underwent fMRI scanning while performing a working-memory n-back task. Iron content was quantified using R2* relaxometry, whereas neuroinflammation was estimated using myo-inositol measured by magnetic resonance spectroscopy. Striatal iron increased non-linearly with age, with linear increases at both ends of adulthood. Whereas higher frontostriatal activity was related to better memory performance independent of age, the link between brain activity and iron differed across age groups. Higher striatal iron was linked to greater frontostriatal activity in younger, but reduced activity in older adults. Further mediation analysis revealed that, after age 40, iron provided unique and shared contributions with neuroinflammation to brain activations, such that neuroinflammation partly mediated brain-iron associations. These findings promote a novel mechanistic understanding of how iron may exert deleterious effects on brain function and cognition with advancing age.
Asunto(s)
Envejecimiento/metabolismo , Encéfalo/metabolismo , Mediadores de Inflamación/metabolismo , Sobrecarga de Hierro/metabolismo , Memoria a Corto Plazo/fisiología , Adulto , Anciano , Envejecimiento/patología , Encéfalo/diagnóstico por imagen , Femenino , Humanos , Sobrecarga de Hierro/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Dopamine (DA) integrity is suggested as a potential cause of individual differences in working memory (WM) performance among older adults. Still, the principal dopaminergic mechanisms giving rise to WM differences remain unspecified. Here, 61 single-nucleotide polymorphisms, located in or adjacent to various dopamine-related genes, were assessed for their links to WM performance in a sample of 1313 adults aged 61-80 years from the Berlin Aging Study II. Least Absolute Shrinkage and Selection Operator (LASSO) regression was conducted to estimate associations between polymorphisms and WM. Rs40184 in the DA transporter gene, SLC6A3, showed allelic group differences in WM, with T-carriers performing better than C homozygotes (p<0.01). This finding was replicated in an independent sample from the Cognition, Brain, and Aging study (COBRA; baseline: n = 181, ages: 64-68 years; 5-year follow up: n = 129). In COBRA, in vivo DA integrity was measured with 11C-raclopride and positron emission tomography. Notably, WM as well as in vivo DA integrity was higher for rs40184 T-carriers at baseline (p<0.05 for WM and caudate and hippocampal D2-receptor availability) and at the 5-year follow-up (p<0.05 for WM and hippocampal D2 availability). Our findings indicate that individual differences in DA transporter function contribute to differences in WM performance in old age, presumably by regulating DA availability.
Asunto(s)
Envejecimiento/genética , Hipocampo/diagnóstico por imagen , Memoria a Corto Plazo/fisiología , Tomografía de Emisión de Positrones , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Anciano , Anciano de 80 o más Años , Alelos , Femenino , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , RaclopridaRESUMEN
Insufficient or excessive dopaminergic tone impairs cognitive performance. We examine whether the balance between transmitter availability and dopamine (DA) D2 receptors (D2DRs) is important for successful memory performance in a large sample of adults (n = 175, 64-68 years). The Catechol-O-Methyltransferase polymorphism served as genetic proxy for endogenous prefrontal DA availability, and D2DRs in dorsolateral prefrontal cortex (dlPFC) were measured with [11C]raclopride-PET. Individuals for whom D2DR status matched DA availability showed higher levels of episodic and working-memory performance than individuals with insufficient or excessive DA availability relative to the number of receptors. A similar pattern restricted to episodic memory was observed for D2DRs in caudate. Functional magnetic resonance imaging data acquired during working-memory performance confirmed the importance of a balanced DA system for load-dependent brain activity in dlPFC. Our data suggest that the inverted-U-shaped function relating DA signaling to cognition is modulated by a dynamic association between DA availability and receptor status.
Asunto(s)
Dopamina/fisiología , Memoria Episódica , Memoria a Corto Plazo/fisiología , Corteza Prefrontal/fisiología , Receptores de Dopamina D2/fisiología , Anciano , Mapeo Encefálico , Catecol O-Metiltransferasa/genética , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tomografía de Emisión de PositronesRESUMEN
Dopamine (DA) modulates corticostriatal connections. Studies in which imaging of the DA system is integrated with functional imaging during cognitive performance have yielded mixed findings. Some work has shown a link between striatal DA (measured by PET) and fMRI activations, whereas others have failed to observe such a relationship. One possible reason for these discrepant findings is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. Moreover, a potential DA-BOLD association may be modulated by task performance. We studied 155 (104 normal-performing and 51 low-performing) healthy older adults (43% females) who underwent fMRI scanning while performing a working memory (WM) n-back task along with DA D2/3 PET assessment using [11C]raclopride. Using multivariate partial-least-squares analysis, we observed a significant pattern revealing positive associations of striatal as well as extrastriatal DA D2/3 receptors to BOLD response in the thalamo-striatal-cortical circuit, which supports WM functioning. Critically, the DA-BOLD association in normal-performing, but not low-performing, individuals was expressed in a load-dependent fashion, with stronger associations during 3-back than 1-/2-back conditions. Moreover, normal-performing adults expressing upregulated BOLD in response to increasing task demands showed a stronger DA-BOLD association during 3-back, whereas low-performing individuals expressed a stronger association during 2-back conditions. This pattern suggests a nonlinear DA-BOLD performance association, with the strongest link at the maximum capacity level. Together, our results suggest that DA may have a stronger impact on functional brain responses during more demanding cognitive tasks.SIGNIFICANCE STATEMENT Dopamine (DA) is a major neuromodulator in the CNS and plays a key role in several cognitive processes via modulating the blood oxygenation level-dependent (BOLD) signal. Some studies have shown a link between DA and BOLD, whereas others have failed to observe such a relationship. A possible reason for the discrepancy is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. We examined the relationship of DA to BOLD response during working memory under three load conditions and found that the DA-BOLD association is expressed in a load-dependent fashion. These findings may help explain the disproportionate impairment evident in more effortful cognitive tasks in normal aging and in those suffering dopamine-dependent neurodegenerative diseases (e.g., Parkinson's disease).
Asunto(s)
Memoria a Corto Plazo/fisiología , Receptores de Dopamina D2/fisiología , Receptores de Dopamina D3/fisiología , Anciano , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiología , Antagonistas de Dopamina , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Red Nerviosa/fisiología , Tomografía de Emisión de Positrones , Corteza Prefrontal/fisiología , Desempeño Psicomotor/fisiología , Racloprida , Radiofármacos , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/efectos de los fármacos , Receptores de Dopamina D3/metabolismo , Tálamo/fisiologíaRESUMEN
OBJECTIVES: The beneficial effects of a physically active lifestyle in aging are well documented. Understanding the factors of importance for physical activity in older adults are therefore essential. Informed by animal and human data linking the dopamine system to motivation and reward processes, we investigated the associations between variations in dopamine genes and objectively measured physical activity and sedentary behaviour. Further, we aimed to verify whether higher age may exacerbate the impact of dopamine genes on physical activity. METHODS: We analyzed data from 504 older adults, 66-87 years, from the population-based Swedish National study on Aging and Care in Kungsholmen (SNAC-K). Physical activity was measured with activPAL accelerometers and DNA was extracted from blood samples for genotyping. We assessed the effects of three dopamine relevant genetic variations (DRD1, DRD2, and DRD3) on daily time in sedentary behavior, light-intensity physical activity and moderate-to-vigorous physical activity using analyses of covariance, adjusting for sex, age and physical function. RESULTS: Higher dopamine receptor efficacy was related to moderate-to-vigorous physical activity, but not to light-intensity physical activity or sedentary time. DRD1 explained 2.7% of variance in moderate-to-vigorous physical activity, with more pronounced effect in people aged ≥80 years, about 10% of explained variance. CONCLUSION: Stronger genetic effects in older adults are in line with the well-established nonlinear effects of dopamine signaling on performance, expected to be exacerbated with aging. Individuals over 80 years, genetically predisposed to lower dopamine receptor efficacy, engaged on average 100 min/week in moderate-to-high physical activity, below the recommended levels beneficial for healthy aging. Our findings highlight that some individuals might need extra support to maintain a physically active lifestyle.
Asunto(s)
Envejecimiento , Ejercicio Físico/fisiología , Receptores Dopaminérgicos/genética , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Envejecimiento/fisiología , Estudios de Cohortes , Humanos , Conducta Sedentaria , SueciaRESUMEN
Episodic memory is a polygenic trait influenced by different molecular mechanisms. We used PET and a candidate gene approach to investigate how individual differences at the molecular level translate into between-person differences in episodic memory performance of elderly persons. Specifically, we examined the interactive effects between hippocampal dopamine D2 receptor (D2DR) availability and candidate genes relevant for hippocampus-related memory functioning. We show that the positive effects of high D2DR availability in the hippocampus on episodic memory are confined to carriers of advantageous genotypes of the brain-derived neurotrophic factor (BDNF, rs6265) and the kidney and brain expressed protein (KIBRA, rs17070145) polymorphisms. By contrast, these polymorphisms did not modulate the positive relationship between caudate D2DR availability and episodic memory.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/genética , Hipocampo/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Memoria Episódica , Receptores de Dopamina D2/metabolismo , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Tomografía de Emisión de PositronesRESUMEN
The dopamine (DA) system plays an important role in cognition. Accordingly, normal variation in DA genes has been found to predict individual differences in cognitive performance. However, little is known of the impact of genetic differences on the link between empirical indicators of the DA system and cognition in humans. The present work used PET with 11C-raclopride to assess DA D2-receptor binding potential (BP) and links to episodic memory, working memory, and perceptual speed in 179 healthy adults aged 64-68 years. Previously, the T-allele of a DA D2-receptor single-nucleotide polymorphism, C957T, was associated with increased apparent affinity of 11C-raclopride, giving rise to higher BP values despite similar receptor density values between allelic groups. Consequently, we hypothesized that 11C-raclopride BP measures inflated by affinity rather than D2-receptor density in T-allele carriers would not be predictive of DA integrity and therefore prevent finding an association between 11C-raclopride BP and cognitive performance. In accordance with previous findings, we show that 11C-raclopride BP was increased in T-homozygotes. Importantly, 11C-raclopride BP was only associated with cognitive performance in groups with low or average ligand affinity (C-allele carriers of C957T, n = 124), but not in the high-affinity group (T-homozygotes, n = 55). The strongest 11C-raclopride BP-cognition associations and the highest level of performance were found in C-homozygotes. These findings show that genetic differences modulate the link between BP and cognition and thus have important implications for the interpretation of DA assessments with PET and 11C-raclopride in multiple disciplines ranging from cognitive neuroscience to psychiatry and neurology.
Asunto(s)
Encéfalo/metabolismo , Antagonistas de los Receptores de Dopamina D2/metabolismo , Memoria Episódica , Memoria a Corto Plazo/fisiología , Desempeño Psicomotor/fisiología , Racloprida/metabolismo , Receptores de Dopamina D2/metabolismo , Anciano , Encéfalo/diagnóstico por imagen , Femenino , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Tomografía de Emisión de Positrones , Receptores de Dopamina D2/genéticaRESUMEN
Individuals differ in how they perceive, remember, and think. There is evidence for the existence of distinct subgroups that differ in cognitive performance within the older population. However, it is less clear how individual differences in cognition in old age are linked to differences in brain-based measures. We used latent-profile analysis on n-back working-memory (WM) performance to identify subgroups in a large sample of older adults (n = 181; age = 64-68 years). Our analysis identified one larger normal subgroup with higher performance (n = 113; 63%), and a second smaller subgroup (n = 55; 31%) with lower performance. The low-performing subgroup showed weaker load-dependent BOLD modulation and lower connectivity within the fronto-parietal network (FPN) as well as between FPN and striatum during n-back, along with lower FPN connectivity at rest. This group also exhibited lower FPN structural integrity, lower frontal dopamine D2 binding potential, inferior performance on offline WM tests, and a trend-level genetic predisposition for lower dopamine-system efficiency. By contrast, this group exhibited relatively intact episodic memory and associated brain measures (i.e., hippocampal volume, structural, and functional connectivity within the default-mode network). Collectively, these data provide converging evidence for the existence of a group of older adults with impaired WM functioning characterized by reduced cortico-striatal coupling and aberrant cortico-cortical integrity within FPN.
Asunto(s)
Envejecimiento/fisiología , Encéfalo/diagnóstico por imagen , Trastornos del Conocimiento/etiología , Trastornos de la Memoria/complicaciones , Memoria a Corto Plazo/fisiología , Anciano , Presión Sanguínea/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Fosfoproteína 32 Regulada por Dopamina y AMPc/genética , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Masculino , Trastornos de la Memoria/diagnóstico por imagen , Trastornos de la Memoria/genética , Recuerdo Mental , Persona de Mediana Edad , Mutación/genética , Pruebas Neuropsicológicas , Oxígeno/sangre , Racloprida/farmacocinética , Receptores de Dopamina D2/genética , Percepción del Tiempo/fisiología , Aprendizaje Verbal/fisiologíaRESUMEN
Evidence suggests that associations between the neurotransmitter dopamine and cognition are nonmonotonic and open to modulation by various other factors. The functional implications of a given level of dopamine may therefore differ from person to person. By applying latent-profile analysis to a large (n = 181) sample of adults aged 64-68 years, we probabilistically identified 3 subgroups that explain the multivariate associations between dopamine D2/3R availability (probed with 11C-raclopride-PET, in cortical, striatal, and hippocampal regions) and cognitive performance (episodic memory, working memory, and perceptual speed). Generally, greater receptor availability was associated with better cognitive performance. However, we discovered a subgroup of individuals for which high availability, particularly in striatum, was associated with poor performance, especially for working memory. Relative to the rest of the sample, this subgroup also had lower education, higher body-mass index, and lower resting-state connectivity between caudate nucleus and dorsolateral prefrontal cortex. We conclude that a smaller subset of individuals induces a multivariate non-linear association between dopamine D2/3R availability and cognitive performance in this group of older adults, and discuss potential reasons for these differences that await further empirical scrutiny.
Asunto(s)
Encéfalo/metabolismo , Cognición/fisiología , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Anciano , Corteza Cerebral/metabolismo , Cuerpo Estriado/metabolismo , Femenino , Hipocampo/metabolismo , Humanos , Análisis de Clases Latentes , Masculino , Memoria/fisiología , Persona de Mediana Edad , Análisis Multivariante , Tomografía de Emisión de Positrones , RaclopridaRESUMEN
D1 and D2 dopamine receptors (D1DRs and D2DRs) may contribute differently to various aspects of memory and cognition. The D1DR system has been linked to functions supported by the prefrontal cortex. By contrast, the role of the D2DR system is less clear, although it has been hypothesized that D2DRs make a specific contribution to hippocampus-based cognitive functions. Here we present results from 181 healthy adults between 64 and 68 y of age who underwent comprehensive assessment of episodic memory, working memory, and processing speed, along with MRI and D2DR assessment with [(11)C]raclopride and PET. Caudate D2DR availability was positively associated with episodic memory but not with working memory or speed. Whole-brain analyses further revealed a relation between hippocampal D2DR availability and episodic memory. Hippocampal and caudate D2DR availability were interrelated, and functional MRI-based resting-state functional connectivity between the ventral caudate and medial temporal cortex increased as a function of caudate D2DR availability. Collectively, these findings indicate that D2DRs make a specific contribution to hippocampus-based cognition by influencing striatal and hippocampal regions, and their interactions.
Asunto(s)
Núcleo Caudado/metabolismo , Hipocampo/metabolismo , Memoria Episódica , Receptores de Dopamina D2/metabolismo , Anciano , Cognición , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Between-person differences in cognitive performance in older age are associated with variations in physical activity. The neurotransmitter dopamine (DA) contributes to cognitive performance, and the DA system deteriorates with advancing age. Animal data and a patient study suggest that physical activity modulates DA receptor availability, but data from healthy humans are lacking. In a cross-sectional study with 178 adults aged 64-68 years, we investigated links among self-reported physical activity, D2/D3 DA receptor (D2/3DR) availability, and cognitive performance. D2/3DR availability was measured with [11C]raclopride positron emission tomography at rest. We used structural equation modeling to obtain latent factors for processing speed, episodic memory, working memory, physical activity, and D2/3DR availability in caudate, putamen, and hippocampus. Physical activity intensity was positively associated with D2/3DR availability in caudate, but not putamen and hippocampus. Frequency of physical activity was not related to D2/3DR availability. Physical activity intensity was positively related to episodic memory and working memory. D2/3DR availability in caudate and hippocampus was positively related to episodic memory. Taken together, our results suggest that striatal DA availability might be a neurochemical correlate of episodic memory that is also associated with physical activity.
Asunto(s)
Envejecimiento/fisiología , Núcleo Caudado/metabolismo , Antagonistas de Dopamina/farmacocinética , Ejercicio Físico/fisiología , Hipocampo/metabolismo , Memoria Episódica , Memoria a Corto Plazo/fisiología , Tomografía de Emisión de Positrones/métodos , Receptores de Dopamina D2/metabolismo , Anciano , Envejecimiento/metabolismo , Núcleo Caudado/diagnóstico por imagen , Femenino , Hipocampo/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Putamen/diagnóstico por imagen , Putamen/metabolismo , Racloprida/farmacocinética , Receptores de Dopamina D3/metabolismoRESUMEN
Previous research shows that associative memory declines more than item memory in aging. Although the underlying mechanisms of this selective impairment remain poorly understood, animal and human data suggest that dopaminergic modulation may be particularly relevant for associative binding. We investigated the influence of dopamine (DA) receptor genes on item and associative memory in a population-based sample of older adults (n = 525, aged 60 years), assessed with a face-scene item associative memory task. The effects of single-nucleotide polymorphisms of DA D1 (DRD1; rs4532), D2 (DRD2/ANKK1/Taq1A; rs1800497), and D3 (DRD3/Ser9Gly; rs6280) receptor genes were examined and combined into a single genetic score. Individuals carrying more beneficial alleles, presumably associated with higher DA receptor efficacy (DRD1 C allele; DRD2 A2 allele; DRD3 T allele), performed better on associative memory than persons with less beneficial genotypes. There were no effects of these genes on item memory or other cognitive measures, such as working memory, executive functioning, fluency, and perceptual speed, indicating a selective association between DA genes and associative memory. By contrast, genetic risk for Alzheimer disease (AD) was associated with worse item and associative memory, indicating adverse effects of APOE ε4 and a genetic risk score for AD (PICALM, BIN1, CLU) on episodic memory in general. Taken together, our results suggest that DA may be particularly important for associative memory, whereas AD-related genetic variations may influence overall episodic memory in older adults without dementia.
Asunto(s)
Envejecimiento/genética , Envejecimiento/psicología , Asociación , Memoria , Polimorfismo de Nucleótido Simple , Receptores Dopaminérgicos/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/psicología , Apolipoproteínas E/genética , Estudios de Cohortes , Femenino , Técnicas de Genotipaje , Humanos , Masculino , Persona de Mediana Edad , Pruebas NeuropsicológicasRESUMEN
Physical activity has been positively associated with gray-matter integrity. In contrast, pro-inflammatory cytokines seem to have negative effects on the aging brain and have been related to dementia. It was investigated whether an inactive lifestyle and high levels of inflammation resulted in smaller gray-matter volumes and predicted cognitive decline across 6 years in a population-based study of older adults (n = 414). Self-reported physical activity (fitness-enhancing, health-enhancing, inadequate) was linked to gray-matter volume, such that individuals with inadequate physical activity had the least gray matter. There were no overall associations between different pro-and anti-inflammatory markers (IL-1ß, IL-6, IL-10, IL-12p40, IL-12p70, G-CSF, and TNF-α) and gray-matter integrity. However, persons with inadequate activity and high levels of the pro-inflammatory marker IL-12p40 had smaller volumes of lateral prefrontal cortex and hippocampus and declined more on the Mini-Mental State Examination test over 6 years compared with physically inactive individuals with low levels of IL-12p40 and to more physically active persons, irrespective of their levels of IL-12p40. These patterns of data suggested that inflammation was particularly detrimental in inactive older adults and may exacerbate the negative effects of physical inactivity on brain and cognition in old age. Hum Brain Mapp 37:3462-3473, 2016. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Envejecimiento/inmunología , Envejecimiento/patología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/inmunología , Sustancia Gris/diagnóstico por imagen , Conducta Sedentaria , Anciano , Anciano de 80 o más Años , Envejecimiento/psicología , Biomarcadores/sangre , Encéfalo/diagnóstico por imagen , Encéfalo/inmunología , Disfunción Cognitiva/sangre , Estudios de Cohortes , Ejercicio Físico/fisiología , Ejercicio Físico/psicología , Femenino , Sustancia Gris/inmunología , Humanos , Inflamación/diagnóstico por imagen , Inflamación/fisiopatología , Inflamación/psicología , Imagen por Resonancia Magnética , Masculino , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Tamaño de los Órganos , Pronóstico , Distribución Aleatoria , AutoinformeRESUMEN
Empathy and vicarious learning of fear are increasingly understood as separate phenomena, but the interaction between the two remains poorly understood. We investigated how social (vicarious) fear learning is affected by empathic appraisals by asking participants to either enhance or decrease their empathic responses to another individual (the demonstrator), who received electric shocks paired with a predictive conditioned stimulus. A third group of participants received no appraisal instructions and responded naturally to the demonstrator. During a later test, participants who had enhanced their empathy evinced the strongest vicarious fear learning as measured by skin conductance responses to the conditioned stimulus in the absence of the demonstrator. Moreover, this effect was augmented in observers high in trait empathy. Our results suggest that a demonstrator's expression can serve as a "social" unconditioned stimulus (US), similar to a personally experienced US in Pavlovian fear conditioning, and that learning from a social US depends on both empathic appraisals and the observers' stable traits.
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Empatía , Miedo/psicología , Aprendizaje , Adolescente , Adulto , Condicionamiento Clásico , Femenino , Respuesta Galvánica de la Piel , Humanos , Masculino , Adulto JovenRESUMEN
Increasing evidence from cross-sectional and longitudinal molecular-genetic studies suggests that effects of common genetic variations on cognitive functioning increase with aging. We review the influence of candidate genes on brain functioning in old age, focusing on four genetic variations that have been extensively investigated: APOE, BDNF, COMT, and KIBRA. Similar to the behavioral evidence, there are reports from age-comparative studies documenting stronger genetic effects on measures of brain functioning in older adults compared to younger adults. This pattern suggests disproportionate impairments of neural processing among older individuals carrying disadvantageous genotypes. We discuss various factors, including gene-gene interactions, study population characteristics, lifestyle factors, and diseases, that need to be considered in future studies and may help understand inconsistent findings in the extant literature.
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Envejecimiento/genética , Apolipoproteínas E/genética , Factor Neurotrófico Derivado del Encéfalo/genética , Encéfalo , Catecol O-Metiltransferasa/genética , Variación Genética , Péptidos y Proteínas de Señalización Intracelular/genética , Fosfoproteínas/genética , Encéfalo/irrigación sanguínea , Encéfalo/fisiología , Femenino , Lateralidad Funcional , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
Losses in dopamine (DA) functioning may contribute to aging-related decline in cognition. Hippocampal DA is necessary for successful episodic memory formation. Previously, we reported that higher DA D2 receptor (D2DR) availability in hippocampus is beneficial for episodic memory only in older carriers of more advantageous genotypes of well-established plasticity-related genetic variations, the brain-derived neurotrophic factor (BDNF, rs6265) and the kidney and brain expressed protein (KIBRA, rs17070145) polymorphisms. Extending our observations to the longitudinal level, the current data show that individuals with one or no beneficial BDNF and KIBRA genotype (n = 80) decline more in episodic memory across five years, without any contribution of losses in hippocampal D2DR availability to memory decline. Although carriers of two beneficial genotypes (n = 39) did not decline overall in episodic memory, losses of hippocampal D2DR availability were predictive of episodic-memory decline among these individuals. Our findings have implications for interventions targeting DA modulation to enhance episodic memory in aging, which may not benefit all older individuals.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Genotipo , Hipocampo , Memoria Episódica , Receptores de Dopamina D2 , Humanos , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Hipocampo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Masculino , Femenino , Anciano , Envejecimiento/fisiología , Envejecimiento/genética , Polimorfismo de Nucleótido Simple , Persona de Mediana Edad , Trastornos de la Memoria/genética , Trastornos de la Memoria/metabolismo , Estudios Longitudinales , Polimorfismo Genético/genética , Pruebas Neuropsicológicas , Anciano de 80 o más Años , Péptidos y Proteínas de Señalización IntracelularRESUMEN
OBJECTIVE: Diabetes is a well-known risk factor for dementia. We investigated the association between (pre)diabetes and older brain age and whether this can be attenuated by modifiable lifestyle behaviors. RESEARCH DESIGN AND METHODS: The study included 31,229 dementia-free adults from the UK Biobank between the ages of 40 and 70. Glycemic status (normoglycemia, prediabetes, or diabetes) was ascertained based on medical history, medication use, and HbA1c measured at baseline. Information on cardiometabolic risk factors (obesity, hypertension, low HDL, and high triglycerides) and lifestyle behaviors (smoking, drinking, and physical activity) was also collected at baseline. Participants underwent up to two brain MRI scans over 11 years of follow-up. Brain age was estimated using a machine learning model based on 1,079 brain MRI phenotypes and used to calculate brain age gap (BAG; i.e., brain age minus chronological age). RESULTS: At baseline, 13,518 participants (43.3%) had prediabetes and 1,149 (3.7%) had diabetes. Prediabetes (ß = 0.22 [95% CI 0.10, 0.34]) and diabetes (2.01 [1.70, 2.32]) were both associated with significantly higher BAG, and diabetes was further associated with significant increase in BAG over time (0.27 [0.01, 0.53]). The association between (pre)diabetes and higher BAG was more pronounced in men and in people with two or more cardiometabolic risk factors. In joint exposure analysis, having a healthy lifestyle (i.e., no smoking, no heavy drinking, and high physical activity) significantly attenuated the diabetes-BAG association. CONCLUSIONS: Diabetes and even prediabetes are associated with accelerated brain aging, especially among men and people with poor cardiometabolic health. However, a healthy lifestyle may counteract this.
RESUMEN
Dopamine decline is suggested to underlie aging-related cognitive decline, but longitudinal examinations of this link are currently missing. We analyzed 5-year longitudinal data for a sample of healthy, older adults (baseline: n = 181, age: 64-68 years; 5-year follow-up: n = 129) who underwent positron emission tomography with 11C-raclopride to assess dopamine D2-like receptor (DRD2) availability, magnetic resonance imaging to evaluate structural brain measures, and cognitive tests. Health, lifestyle, and genetic data were also collected. A data-driven approach (k-means cluster analysis) identified groups that differed maximally in DRD2 decline rates in age-sensitive brain regions. One group (n = 47) had DRD2 decline exclusively in the caudate and no cognitive decline. A second group (n = 72) had more wide-ranged DRD2 decline in putamen and nucleus accumbens and also in extrastriatal regions. The latter group showed significant 5-year working memory decline that correlated with putamen DRD2 decline, along with higher dementia and cardiovascular risk and a faster biological pace of aging. Taken together, for individuals with more extensive DRD2 decline, dopamine decline is associated with memory decline in aging.